ERK/MAPK activation is a critical component of the signaling mechanisms that regulate synaptic plasticity and the formation of long-term memories in a large variety of species. The substrates for ERK phosphorylation that contribute to the induction of LTP and long-term memory formation are largely unknown. One intriguing possibility is the potassium channel, Kv4.2, which forms a transient A-type potassium current (IA) in pyramidal neurons of the hippocampus and regulates membrane excitability. ERK activation decreases IA and enhances the amplitude of back-propagating action potentials in pyramidal cell dendrites. These changes may play an important role in mediating learning-related neuronal plasticity in the brain. This proposal will investigate the role of ERK phosphorylation of Kv4.2 in the hippocampus in the formation of memories and modulation of synaptic plasticity. Antibodies to phosphorylated Kv4.2 will be developed and used to assess any changes in ERK-mediated Kv4.2 phosphorylation following induction of LTP as well as a hippocampus-dependent learning task, contextual fear-conditioning. The role of Kv4.2 in synaptic plasticity and learning and memory will be further evaluated using Kv4.2 knockout mice. This research will enhance our understanding of the molecular changes that support learning and synaptic plasticity, as well as provide insights into disease states such as mental retardation.